U.S. patent application number 11/013387 was filed with the patent office on 2005-10-13 for fluorescent sensor on basis of multichannel structures.
This patent application is currently assigned to INSTITUTE FOR ROENTGEN OPTICS. Invention is credited to Avotynsh, Nikolai O., Khamizov, Ruslan Kh., Kumakhov, Muradin A., Mikhin, Victor A., Nikitina, Svetlana V., Zhiguleva, Tatiana I..
Application Number | 20050225756 11/013387 |
Document ID | / |
Family ID | 34910156 |
Filed Date | 2005-10-13 |
United States Patent
Application |
20050225756 |
Kind Code |
A1 |
Khamizov, Ruslan Kh. ; et
al. |
October 13, 2005 |
Fluorescent sensor on basis of multichannel structures
Abstract
Sensor for use in highly sensitive analytical devices for
qualitative and quantitative analysis of natural waters and
technology-related solutions, containing low concentrations of
components determined. Design of a sensor provides for
simplification and costs reduction of its manufacture, widening
range of solutions analyzed, improvement of their kinetic
characteristics and increase in analysis sensitivity. Sensor has
multichannel structure in a form of a piece 1 of a polycapillary
tube with through capillaries forming microchannels filled up with
two layers of immiscible substances. One layer (4) is formed of
water or aqueous solution, and another layer (3) is formed of
organic substance. The first of the layers in microchannels
contains sorbent microgranules 5.
Inventors: |
Khamizov, Ruslan Kh.;
(Moscow, RU) ; Kumakhov, Muradin A.; (Moscow,
RU) ; Nikitina, Svetlana V.; (Moscow, RU) ;
Mikhin, Victor A.; (Maisky, RU) ; Zhiguleva, Tatiana
I.; (Moscow, RU) ; Avotynsh, Nikolai O.;
(Moscow region, RU) |
Correspondence
Address: |
MCDERMOTT WILL & EMERY LLP
600 13TH STREET, N.W.
WASHINGTON
DC
20005-3096
US
|
Assignee: |
INSTITUTE FOR ROENTGEN
OPTICS
|
Family ID: |
34910156 |
Appl. No.: |
11/013387 |
Filed: |
December 17, 2004 |
Current U.S.
Class: |
356/246 ;
356/344; 356/36 |
Current CPC
Class: |
G01N 21/6452 20130101;
G01N 21/645 20130101 |
Class at
Publication: |
356/246 ;
356/344; 356/036 |
International
Class: |
G01N 021/01 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 9, 2004 |
RU |
2004110692 |
Claims
What is claimed is:
1. Fluorescent sensor on the basis of multichannel structure,
comprising microchannels with sorbent microgranules placed into
microchannels on the side of one of the end faces of multichannel
structure, characterized in that the multichannel structure is a
piece of polycapillary tube with through capillaries forming the
microchannels, the microchannels being filled with two layers of
immiscible substances, one of which is formed of water or aqueous
solution, and another is formed of organic substance, said sorbent
microgranules located in microchannels being situated in aqueous or
aqueous solution layer.
2. Sensor according to claim 1, characterized in that said sorbent
microgranule is located in aqueous or aqueous solution layer with
possibility of free movement.
3. Sensor according to claim 2, characterized in that said organic
substance forming one of the layers filling up microchannels is in
a liquid phase and different microchannels contain granules of
different sorbents.
4. Sensor according to claim 2, characterized in that said organic
substance forming one of the layers filling up microchannels is in
a liquid phase and different microchannels contain granules of one
and the same sorbent.
5. Sensor according to claim 2, characterized in that said organic
substance forming one of the layers filling up microchannels is in
a solid phase and different microchannels contain granules of one
and the same sorbent.
6. Sensor according to claim 2, characterized in that said organic
substance forming one of the layers filling up microchannels is in
a solid phase and different microchannels contain granules of
different sorbents.
7. Sensor according to claim 3, characterized in that said organic
substance forming one of the layers filling up microchannels is
optically transparent or radiolucent, and said length of
polycapillary tube is made with possibility of transporting,
correspondingly, optical or X ray radiation.
8. Sensor according to claim 7, characterized in that said
multichannel structure is made in the form of a straight length of
polycapillary tube.
9. Sensor according to claim 7, characterized in that said
multichannel structure is made in the form of a curved length of
polycapillary tube.
10. Sensor according to claim 7, characterized in that said
multichannel structure is made as a length of polycapillary tube in
the form of a tablet having length less than its transverse
dimensions.
11. Sensor according to claim 4, characterized in that said organic
substance forming one of the layers filling up microchannels is
optically transparent or radiolucent, and said length of
polycapillary tube is made with possibility of transporting,
correspondingly, optical or X ray radiation.
12. Sensor according to claim 11, characterized in that said
multichannel structure is made in the form of a straight length of
polycapillary tube.
13. Sensor according to claim 11, characterized in that said
multichannel structure is made in the form of a curved length of
polycapillary tube.
14. Sensor according to claim 11, characterized in that said
multichannel structure is made as a length of polycapillary tube in
the form of a tablet having length less than its transverse
dimensions.
15. Sensor according to claim 5, characterized in that said organic
substance forming one of the layers filling up microchannels is
optically transparent or radiolucent, and said length of
polycapillary tube is made with possibility of transporting,
correspondingly, optical or X ray radiation.
16. Sensor according to claim 15, characterized in that said
multichannel structure is made in the form of a straight length of
polycapillary tube.
17. Sensor according to claim 15, characterized in that said
multichannel structure is made in the form of a curved length of
polycapillary tube.
18. Sensor according to claim 15, characterized in that said
multichannel structure is made as a length of polycapillary tube in
the form of a tablet having length less than its transverse
dimensions.
19. Sensor according to claim 6, characterized in that said organic
substance forming one of the layers filling up microchannels is
optically transparent or radiolucent, and said length of
polycapillary tube is made with possibility of transporting,
correspondingly, optical or X ray radiation.
20. Sensor according to claim 19, characterized in that said
multichannel structure is made in the form of a straight length of
polycapillary tube.
21. Sensor according to claim 19, characterized in that said
multichannel structure is made in the form of a curved length of
polycapillary tube.
22. Sensor according to claim 19, characterized in that said
multichannel structure is made as a length of polycapillary tube in
the form of a tablet having length less than its transverse
dimensions.
23. Sensor according to claim 1, characterized in that said organic
substance forming one of the layers filling up microchannels is
optically transparent or radiolucent, and said length of
polycapillary tube is made with possibility of transporting,
correspondingly, optical or X ray radiation.
24. Sensor according to claim 23, characterized in that said
multichannel structure is made in the form of a straight length of
polycapillary tube.
25. Sensor according to claim 23, characterized in that said
multichannel structure is made in the form of a curved length of
polycapillary tube.
26. Sensor according to claim 23, characterized in that said
multichannel structure is made as a length of polycapillary tube in
the form of a tablet having length less than its transverse
dimensions.
27. Sensor according to claim 2, characterized in that said organic
substance forming one of the layers filling up microchannels is
optically transparent or radiolucent, and said length of
polycapillary tube is made with possibility of transporting,
correspondingly, optical or X ray radiation.
28. Sensor according to claim 27, characterized in that said
multichannel structure is made in the form of a straight length of
polycapillary tube.
29. Sensor according to claim 27, characterized in that said
multichannel structure is made in the form of a curved length of
polycapillary tube.
30. Sensor according to claim 27, characterized in that said
multichannel structure is made as a length of polycapillary tube in
the form of a tablet having length less than its transverse
dimensions.
Description
FIELD OF THE INVENTION
[0001] The invention relates to the field of chemical and
biological analysis and may be used for development of highly
sensitive analytical devices for qualitative and quantitative
analysis of aqueous and organic solutions, namely, natural waters
and technology-related solutions containing low concentrations of
inorganic and organic components being determined, as well as
solutions containing biologically active compounds.
BACKGROUND ART
[0002] Chemical and biological sensors [1-5] are sensing elements
providing direct information on ion or molecular composition of the
medium (solution) the sensor is immersed in, without its sampling
and preconditioning for analysis. Sensors are used in combination
with any analytical registering device. To be used for
determination of microcomponents in solutions, the sensors should
possess ability for selective adsorption (sorption) of components
being determined from these solutions, as well as ability to
accumulate these components to concentrations exceeding the
detection limits of the registering analytical device. If it is
necessary to provide for routine monitoring (tracking the changes
in microcomponents concentrations) of water stream being analyzed
in in-line (right in the stream) or on-line (in bypass stream)
modes, the sensors should possess satisfactory kinetic response--an
ability for fast attainment of equilibrium accumulation in a
characteristic time lesser than that of substantial concentration
changes in the stream analyzed. The heart of any sensor is
immobilized (attached to accessible surface of the sensor) active
substance, able to interact selectively with components being
determined.
[0003] Sensor varieties comprise chemical or biological chips
[3-5]--analytical sensors containing set of different active
substances in one sensor or set of sensors having different
characteristics, each one containing active substance of a certain
type. Chemical or biological chip provides information on the
mixtures being analyzed not in the numerical form as a response to
single measurement, but in the form of some
pattern--two-dimensional or three-dimensional image being the
compact and exact characteristic ("fingerprint") of the mixture in
whole. Although each point of such an image, characterizing
presence and concentration of one or another substance, may not be
quite correct, the chips allow to ensure essentially full
selectivity and unambiguity in analysis due to multiple duplication
of such points and to additional information in the form of
integral image. The development of chemical and biological chips
have began just recently. In literature, notions of electronic
(chemical) "nose" or electronic (chemical) "tongue" are also used
in respect of chemical chips, in order to underline that
selectivity, similar to living organisms, is attained due to a set
of sensors having different characteristics [6].
[0004] Different types of known chemical sensors [1] include:
electrochemical (including potentiometric transducers, such as
ion-selective electrodes); electrical sensors on basis of field
transistors and other devices, magnetic sensors, thermometric
sensors, as well as sensors sensitive to selective component
accumulation due to changes in piezoelectrical or acoustical
characteristics. Principal drawback of said analytical sensors lies
in limited range of the components determined--virtually for each
component separate sensor should be designed having certain type of
active substance. Besides, it is difficult to create biological
sensors on base of approaches specified.
[0005] Said drawbacks are eliminated in optical and X ray
fluorescent sensors [2], wherein active substance may possess group
selectivity to a large number of inorganic, organic or biologically
active components. After sorption of these components on
immobilized active substance, accessible surface with active
substance is treated with exciting radiation by means of UV laser
or X ray radiation source. In the first case, fluorescence
(luminescence) spectrum is observed in the visible region, and in
the second one--X ray fluorescence spectrum. Owing to analytical
possibilities of methods specified, allowing to observe separately
spectral bands of the components being determined, possibility
appears for simultaneous analysis of multicomponent mixtures.
[0006] Fluorescent sensors are known in which active substance,
interacting with environment components being determined, is
applied on (impregnated) or chemically linked to membranes or
microgranules of solid porous materials forming sorption layer
comprising a large number of monolayers [7]. Principal drawback of
said devices lies in the fact that they may not be used as chips
allowing to obtain a separate signal from each active surface
portion of the sensor.
[0007] The drawback specified is eliminated through use of
monolayers of microgranules of solid active substances or
microvessels with liquid active substances. Fluorescent sensors
(biochips) are known [8, 9], wherein active substances, selectively
interacting with biologically active macromolecules from the medium
being analyzed, are placed in a certain regular manner into
channels or pinholes, cut in a special carrier made of glass,
quartz, ceramics, plastic or other inert material by lithography or
other methods. At present, number of microareas with active
substances attainable in such devices doesn't exceed several
thousand units. This leads to decrease in sensitivity (detection
limits) of the analysis utilizing X-ray fluorescence method.
[0008] The most close to the device proposed in technical essence
is a fluorescent sensor on basis of multichannel structure, as
described in [10]. This sensor is obtained by sintering of a bundle
comprising a large number of optical fibers, each one consisting of
two coaxial layers formed by two grades of glass or quartz or
polymer. One of the end faces of the bundle obtained is treated
with chemical substances for etching the internal layers (to a
small depth ca. 10 micron) in each fiber, and microspheres of solid
active sorbent substance or solid inert substance coated with an
active reagent are placed and fixed in the channels formed
("microwells"). Monolayer of microgranules is obtained by way of
one microsphere being placed to each channel. Distribution of
microspheres in microchannels is achieved by using ultrasonic or
other agitation from suspension in volatile liquid, which is then
evaporated. Fixation of microspheres in channels is achieved
through synthesis of films on surface of the multichannel structure
end face from organic substances having different permeability.
Another method of fixation involves distribution of microgranules
in channels from liquid, in which granule doesn't swell, followed
by treatment with another liquid, in which said granule swells and
gets fixed. Thus, the device described is a fluorescent sensor on
basis of multichannel structures having open microchannels, each
one containing sorbent microgranule, in one of the end faces.
[0009] Principal drawbacks of said device comprise: complex
manufacturing technology, unsatisfactory kinetic characteristics,
associated with blocking of substantial part of microgranules
surface during their fixation, as well as limited nature of
analytical objects, associated with necessity to restrict swelling
limits of microgranules in order to preserve integrity of the
device. Another drawback of the device specified lies in
impossibility to achieve low detection limits for X-ray fluorescent
analysis with the use of such sensors. This is due to the fact of
external and internal layers of optical fibers being comparable in
thickness, so that number of sorbent granules per unit surface of
the end face is insignificant, resulting, correspondingly, in
equally insignificant density of adsorbed substance being analyzed
per unit surface of the end face.
SUMMARY OF THE DISCLOSURE
[0010] The invention proposed is aimed at the achievement of
technical result consisting in simplification and reducing the
costs of fluorescent sensor manufacturing, widening the range of
solutions analyzed with one and the same device, improvement in
kinetic characteristics of analytical methods utilizing fluorescent
sensor, and increase in analysis sensitivity using X-ray
fluorescence method.
[0011] Fluorescent sensor according to the invention proposed,
similar to the most close sensor known from [10], is made on base
of multichannel structure with microchannels and comprises sorbent
microgranules placed into microchannels on the side of one of the
end faces of the multichannel structure.
[0012] To achieve this technical result, said multichannel
structure in the fluorescent sensor proposed, as distinct from the
most close known one, comprises a length of polycapillary tube with
through capillaries forming said microchannels. Microchannels are
filled with two layers of immiscible substances. One of the layers
consists of water or aqueous solution. This layer contains sorbent
microgranule. The second layer consists of organic substance.
[0013] Thickness of aqueous layer or layer of aqueous solution
filling the microchannels, with sorbent microgranule located
therein, doesn't exceed 3 millimeters. The reason of this is lies
in the fact that further increase in thickness of said layer brings
about no improvements in partitioning of said layer and organic
substance layer, that is, makes no further contribution to better
isolation of sorbent granule from the organic substance, but
results instead in the increase of analysis time due to a growth in
diffusion time of components being sorbed in aqueous or aqueous
solution layer.
[0014] Sorbent microgranule in aqueous or aqueous solution layer is
arranged advantageously with possibility of its free movement. This
ensures possibility of free access of the components being sorbed
to the total sorbent microgranules surface, that is, improves
kinetic characteristics of the sensor in a wide range of solutions
analyzed, in which microgranules may have different swelling
properties.
[0015] Microgranules placed into different microchannels may belong
to one and the same or different sorbents.
[0016] The first embodiment is better used for development of
sensors allowing for analysis of solutions containing small number
of components having independent fluorescent signals.
[0017] The second embodiment is better used for development of
chips allowing to perform analysis of multicomponent solutions
containing large number of components with interfering fluorescent
signals.
[0018] It is expedient to make polycapillary tube, in particular,
of glass or quartz.
[0019] This will allow to simplify and reduce costs of manufacture
of the source polycapillary tubes, including utilization of
technologies developed for these materials.
[0020] At that, polycapillary tube for analysis of acid and neutral
solutions is better made of glass, as the more cheap material.
[0021] For analysis of alkaline solutions, interacting chemically
with glass, it is better to make polycapillary tube of quartz.
[0022] In particular, it is expedient to make polycapillary tube
with thickness of microchannel walls by an order of magnitude
smaller than their transverse dimensions.
[0023] This relates to the sensors for X-ray fluorescent analysis
built up on the additive fluorescence effect from all sorbent
granules in the device.
[0024] At that, when producing chemical and biological chips for
luminescent spectral analysis in the visible region, the
polycapillary tube may be made with larger walls thickness in order
to avoid merging of signals from each microgranule of corresponding
sorbent.
[0025] Multichannel structure may be made in the form of straight
or curved length of polycapillary tube.
[0026] The first embodiment is better used for development of
fluorescent sensors, incorporated into analytical units of devices
having no special requirements to their compactness associated with
a need to analyze solution streams in hard-to-reach points. In this
embodiment, the exciting radiation is applied to the end face with
microchannels having sorbent microgranules located therein, and
source of the exciting radiation is accommodated within said
unit.
[0027] The second embodiment is better used for development of
fluorescent sensors, incorporated into compact analytical units of
devices placed in the stream of the solution being analyzed in
hard-to-reach points. In this embodiment, the exciting radiation is
applied to opposite end face, where there are no sorbent
microgranules, and the source of the exciting radiation is
accommodated outside of said unit.
[0028] However, depending on particular conditions of sensor
application, the embodiment of multichannel structure in the form
of a straight length of polycapillary tube may turn out to be
expedient also in the case of the exciting radiation being supplied
from the side of the end face containing no sorbent granules.
Conversely, the embodiment of the multichannel structure in the
form of a curved length of polycapillary tube may become expedient
in the case of the exciting radiation being supplied to the end
face with microchannels containing sorbent microgranules.
[0029] For multichannel structures made both in the form of
straight and curved length of the polycapillary tube, utilization
of the sensor is also possible, in which sensor of excited
luminescent radiation is located on the side of the end face
containing no sorbent microgranules.
[0030] Multichannel structure may be also made as a length of
polycapillary tube in the form of a tablet, with length smaller
than its transverse dimensions.
[0031] This embodiment is expedient for more compact analytical
devices regardless of the end face of polycapillary tube to which
the exciting radiation is supplied.
[0032] Organic substance forming one of the above layers filling up
microchannels may be either in solid or liquid phase.
[0033] The first embodiment is better used for development of
fluorescent sensors being arranged in analytical units of the
devices in upright position, with aqueous solution layer situated
below the layer of organic substance.
[0034] The second embodiment is better used for development of
fluorescent sensors arranged in analytical units of the devices in
an arbitrary position. This embodiment is also preferable in the
case when sorbent microgranule may interact not only with
substances in aqueous solution, but also with substances in the
organic layer.
[0035] In all the cases of sensor utilization contemplating
accommodation of the source of exciting radiation or sensor of
excited luminescent radiation on the side of the end face
containing no sorbent granules, the organic substance forming one
of the above layers filling up the microchannels (that is, layer
adjacent to said end face of the sensor) should be transparent for
corresponding radiation (X ray or optical). At that, the length of
polycapillary tube should be made with possibility of transporting
said radiation.
[0036] Thus, the sensor on basis of multichannel structure is
proposed. The sensor contains microchannels with sorbent
microgranules placed into microchannels on the side of one of the
end faces of multichannel structure. The multichannel structure is
a length of polycapillary tube with through capillaries forming
said microchannels. The latter being filled with two layers of
immiscible substances, one of which is formed of water or aqueous
solution, and another--of organic substance. Said sorbent
microgranules located in microchannels being situated in aqueous or
aqueous solution layer.
[0037] Several features of embodiment of a sensor in various
special cases have been described:
[0038] sorbent microgranule may be located in aqueous or aqueous
solution layer with possibility of free movement;
[0039] microgranules placed into different microchannels may belong
to one and the same or different sorbents;
[0040] organic substance forming one of the layers filling up
microchannels may be either in solid or liquid phase;
[0041] said organic substance may be optically transparent or
radiolucent, and the length of polycapillary tube may be made with
possibility of transporting, correspondingly, optical or X ray
radiation;
[0042] polycapillary tube may be made, in particular, of glass or
quartz;
[0043] polycapillary tube may have thickness of its microchannels
walls smaller by an order of magnitude than their transverse
dimensions;
[0044] thickness of said aqueous or aqueous solution layer
containing sorbent microgranules doesn't exceed 3 millimeters.
[0045] Also three special cases of embodiment of the mentioned
multichannel structure have above been described: in the form of a
straight or curved length of polycapillary tube and in the form of
a tablet.
[0046] It is expediently, that the said organic substance is
optically transparent or radiolucent, and the length of
polycapillary tube may be made with possibility of transporting,
correspondingly, optical or X ray radiation. In this case, it is
possible any of three said embodiments of the mentioned
microchannel structure: in the form of a straight or curved length
of polycapillary tube and in the form of a tablet.
[0047] Also it is expediently, the allocation of sorbent
microgranules in aqueous or aqueous solution layer with possibility
of free movement. At such allocation of sorbent microgranules the
said organic substance also may by optically transparent or
radiolucent, and the length of polycapillary tube may be made with
possibility of transporting, correspondingly, optical or X ray
radiation. At the specified allocation of sorbent microgranules it
is also possible any of three mentioned embodiments of the
microchannel structure: in the form of a straight or curved length
of polycapillary tube and in the form of a tablet.
[0048] Along with the specified allocation of sorbent microgranules
in aqueous or aqueous solution layer with possibility of free
movement, organic substance forming one of the layers filling up
microchannels may be either in solid or liquid phase, and different
microchannels can contain granules of one and the same or different
sorbents. In these cases multichannel structure may be made in the
form of a straight or curved length of polycapillary tube and in
the form of a tablet.
[0049] In all listed above cases of embodiment of the mentioned
multichannel structure (in the form of a straight or curved length
of polycapillary tube and in the form of a tablet), it is
expediently, to make polycapillary tube with thickness of its
microchannels walls smaller by an order of magnitude than their
transverse dimensions, and thickness of said aqueous or aqueous
solution layer containing sorbent microgranules not exceed 3
millimeters.
[0050] Additional advantages and aspects of the disclosure will
become readily apparent to those skilled in the art from the
following detailed description, wherein embodiments of the present
disclosure are shown and described, simply by way of illustration
of the best mode contemplated for practicing the present
disclosure. As will be described, the disclosure is capable of
other and different embodiments, and its several details are
susceptible of modification in various obvious respects, all
without departing from the spirit of the disclosure. Accordingly,
the drawings and description are to be regarded as illustrative in
nature, and not as limitative.
BRIEF DESCRIPTION OF THE DRAWINGS
[0051] The following detailed description of the embodiments of the
present disclosure can best be understood when read in conjunction
with the following drawings, in which the features are not
necessarily drawn to scale but rather are drawn as to best
illustrate the pertinent features, wherein:
[0052] FIG. 1 demonstrates an embodiment of the device comprising
multichannel structure in the form of a length of straight
polycapillary tube.
[0053] FIG. 2 demonstrates an embodiment of the device comprising
multichannel structure in the form of a length of curved
polycapillary tube.
[0054] FIG. 3 demonstrates an embodiment of the device in which
multichannel structure is made in the form of a tablet.
[0055] FIG. 4 shows schematically an example of a sensors
manufacturing plant.
[0056] FIG. 5 shows photomicrographs of open lower end face of the
polycapillary tube.
[0057] FIG. 6 demonstrates an example of structure of a special cap
having microporous bottom forming the lower part of the sensor.
[0058] FIG. 7 shows potentiometric curves for testing the
operability of sensors.
[0059] FIG. 8 shows utilization of sensor proposed incorporated
into analytical device for X-ray fluorescent analysis of
solutions.
[0060] FIG. 9 shows utilization of sensor proposed incorporated
into analytical device for luminescent analysis of solutions in the
visible region.
[0061] FIG. 10 shows utilization of sensor proposed with optically
transparent organic substance forming one of the layers filling up
microchannels, incorporated into analytical device for X-ray
fluorescent analysis of solutions.
[0062] FIG. 11 shows utilization of sensor proposed with optically
transparent organic substance forming one of the layers filling up
microchannels, incorporated into analytical device for luminescent
analysis of solutions in the visible region.
[0063] FIGS. 12-14 show X ray fluorescence spectra registered
during analysis of different solutions utilizing the sensor
proposed on basis of multichannel structure.
DETAILED DISCLOSURE OF THE EMBODIMENTS
[0064] Fluorescent sensor on basis of multichannel structures
according to the invention proposed is constructed as follows. A
length 1 of polycapillary tube (FIG. 1), for example, made of glass
or quartz, with hundreds of thousand of through capillaries
(microchannels) of the same size from units to hundreds micron in
transverse section, is hermetically sealed on the side of upper end
face with a layer 2 of inert material. Within each microchannel two
substance layers are situated. The upper layer 3 is formed of
organic substance, and the lower layer 4 is formed of water or
aqueous solution. In this layer, sorbent microgranule 5 is located
under conditions of free movement, having maximum diameter smaller
(for example, by 10-20%) than the internal diameter of
microchannel. Lower end face is covered with a layer 6 of inert
filtering material having diameter of pores smaller than the
diameter of sorbent microgranules.
[0065] Multichannel polycapillary structure forming a part of the
sensor proposed, in this and other particular embodiments described
below may be manufactured, for example, according to methods
described in patents [11, 12]. It is possible also to use
technology employed in manufacture of polycapillary chromatographic
columns, as described in patent [13]. Said technology is preferred
if there is a need to ensure small dispersion in cross-sectional
dimensions of microchannels.
[0066] Fluorescent sensor on basis of multichannel structures in a
variant shown in FIG. 2, comprises also a length 1 of polycapillary
tube, hermetically sealed on the upper end face with a layer 2 of
inert material. The microchannels formed by capillaries contain an
internal layer 3 of organic substance, and a layer 4 of water or
aqueous solution with sorbent microgranule 5 freely located in it.
Layer 6 of inert filtering material covers the end face on the side
of aqueous or aqueous solution layer. The distinctive feature of
the device embodiment according to FIG. 2 lies in that it is made
in the form of a tablet, manufactured from a length of
polycapillary tube, having length smaller than diameter of its end
face.
[0067] In the embodiment shown in FIG. 3, fluorescent sensor
proposed on basis of multichannel structures comprises also a
length 1 of polycapillary tube, hermetically sealed or covered on
one of the end faces with a layer 7 of inert material. The
microchannels formed by capillaries contain an internal layer 8 of
organic substance, and a layer 4 of water or aqueous solution with
sorbent microgranule 5 freely located in it. Layer 6 of inert
filtering material is covering the end face on the side of aqueous
or aqueous solution layer.
[0068] The distinctive feature of the device according to this
embodiment lies in that it is made of a curved length of
polycapillary tube. Other features of this device embodiment
consist in that the layer 7 of inert material and internal layer 8
of organic substance are radiolucent and/or optically transparent,
and that said length of polycapillary tube is made with possibility
of transporting, correspondingly, optical or X ray radiation.
[0069] In the first case, aggregate microchannels filled up with
organic substance serve as a light guide, and in the second one--as
a bender, that is, means for transmission and turning of X ray
radiation. In this case, total external reflection of radiation
from microchannels walls is utilized, and geometry of
microchannels, properties of walls material and of organic
substance are chosen so as to satisfy the conditions for multiple
total external reflection [15, 16].
[0070] Table 1 lists examples of materials used for manufacturing
of layer 2 for hermetical sealing or covering of one of the end
faces of a straight length of the polycapillary tube (including
short lengths, if sensor is made in the form of a tablet) in the
cases shown in FIG. 1 and FIG. 2.
1TABLE 1 Inert material Nos. for layer 2 Method of end face
covering 1 Sealant stable to Sealing with polymerizable sealant
organic solvents 2 Oil- and pertol- Use of sealing head with rubber
gasket resistant rubber 3 Silicone Use of sealing head with
silicone gasket 4 Liquid glass Sealing with liquid glass followed
by hardening 5 Liquid glass + Sealing with liquid glass and
additional rubber sealing-in using sealing head with rubber gasket
6 Liquid glass + Sealing with liquid glass and additional
polyethylene sealing-in using sealing head with polyethylene gasket
7 Liquid glass + Sealing with liquid glass and additional
polypropylene sealing-in using sealing head with polypropylene
gasket 8 Liquid glass + Sealing with liquid glass and additional
teflon sealing-in using sealing head with teflon gasket 9 Paraffin
+ rubber (or Sealing with liquid paraffin with silicone) subsequent
packing 10 Paraffin + Sealing with liquid paraffin with
polyethylene (or subsequent packing polypropylene or teflon)
[0071] Table 2 lists examples of inert radiolucent
(<<RL>>) and/or transparent to ultraviolet on
(<<UVT>>) materials for manufacturing of layer 7 for
hermetical sealing or covering of the end faces of a length of
curved polycapillary tube in the case shown in FIG. 3.
2TABLE 2 Nos. Inert material for layer 7 Method of the end face
covering 1 RL, UVT Sealing of the end face with subsequent
Thermoplastic hot-melt setting adhesives on basis of polyethylene 2
RL, UVT Sealing with adhesive applcation on the Polyethylene film +
film (engaging the upper part of outer thermoplastic adhesives wall
of polycapillary tube) followed (solutions on basis by curing of
polystyrene) 3 RL, UVT Sealing with adhesive applcation on the
Cellophane film + film (engaging the upper part of outer
thermoplastic adhesives wall of polycapillary tube) followed
(solutions on basis by curing of polystyrene) 4 RL Sealing of the
end face followed by Thermoplastic hot-melt setting adhesives on
basis of ethylene-vinylacetate copolymer
[0072] Table 3 lists examples of organic substances forming
internal layer 3 of sensors made of a straight length of
polycapillary tube, including those in the form of a tablet, shown
in FIG. 1 and FIG. 2, or internal layer 8 of sensor made of a
curved length of polycapillary tube shown in FIG. 3.
3TABLE 3 Physical state: Liquid--<<L>>;
Solid--<<S>>; Radiolucent--<<RL>>;
Transparent for ultraviolet Nos. Substance
radiation--<<UVT>> 1 Hexane L, RL, UVT 2 Heptane L, RL,
UVT 3 Octane L, RL, UVT 4 Gasoline L, RL, UVT 5 White spirit L, RL,
UVT 6 Benzene L, RL 7 Toluene L, RL 8 Paraffin S, RL 9
Polyacrylamide S, RL 10 Polyacrylonitrile S, RL 11 Polystyrene S,
RL
[0073] Table 4 lists examples of sorbents constituting the
microgranules 5 placed into layer 4 of water or aqueous
solution.
4TABLE 4 Nos. Sorbent material Functional group 1 Strong-acid gel
and macroporous cationites: KU- --SO.sub.3.sup.- 2, KU-23,
Dowex-50, Dowex-HCR, Dowex- MSC, Dowex-Marathon C, Purolite C100,
Amberlite GOL, Amberjet, Lewatit S, Lewatit SP 2 Weak-acid gel and
macroporous cationites: --COO.sup.- KB-2, KB-4, Dowex MAC, Purolite
C105, Amberlite IRC, Lewatit SNP 3 Strong-base gel and macroporous
anionites: --N(R.sub.4).sup.+ AV-17, AV-171, Dowex-2, Dowex-MSA,
Purolite A400, Amberlite IRA, Lewatit M 4 Weak-base gel and
macroporous anionites: --NH.sub.k(R.sub.4-k).sup.+ AN-31, AN-221,
AN-511, Dowex MWA, where k = 1, 2, 3 Purolite A100, Lewatit MP 5
Gel and macroporous polyampholytes: --SO.sub.3.sup.- +
--NH.sub.k(R.sub.4-k).sup.+ ANKB-50, Tulsion or --COO.sup.- +
--NH.sub.2 6 Selective sorbents for analytical chemistry of the
--C(R).dbd.N--OH; <<Polysorb>> type --CO--N(R).dbd.OH;
--C(OH)--C(R).dbd.N--OH; --N(R)--C(S)--S(Na); --N--(NO)--ONH.sub.4;
--CH.sub.2(R)--N(CH.sub.2COONa).sub.2, where R denotes organic
radical, and other amidooxime, hydrazine, dithiozone, diacetate
groups 7 Impregnated sorbents Impregnation with: liquid ionites:
complexing organic agents, extractants. 8 Neutral polymeric
matrices with subsequent Crosslinking: chemical cross-linking of
functional group oligomers and monomers with ion-exchange groups:
complexing organic agents and extractants 9 Inorganic sorbents
containing no components to Aluminosilicate, oxide, phosphate be
determined 10 Sorbent supports for affinity chromatography of
CM-celulose, biopolymers DEAE-celulose, Agarose, Sephadex,
Hydroxyalkylmethacrylate, Polyvinylacetate
[0074] Table 5 lists examples of inert filtering materials for
layer 6 covering the end face on the side of aqueous or aqueous
solution layer.
5TABLE 5 Network--<<N>>, Membrane--<<M>>
Radiolucent--<<RL>> Transparent to ultraviolet Material
radiation--<<UVT>- ;> (a film 1-20 micron thick)
Transparent in the Nos. diameter of openings - 1-10 micron visible
region--<<VT>> 1 Caprone N, RL, UVT 2 Nylon N, RL, UVT
3 Glass fibre cloth N 4 Polyacetate M, RL, UVT 5 Polyethylene M,
RL, UVT, VT 6 Teflon M, RL, UVT, VT 7 Polypropylene M, RL, UVT, VT
8 Cellophane M, RL, UVT, VT
[0075] In manufacture of the fluorescent sensor proposed on basis
of multichannel polycapillary structure, capillary rise effect may
be utilized for liquids possessing wetting ability. Manufacturing
of device with a layer of liquid organic substance in microchannels
comprises following stages.
[0076] A. Sorbent material is preliminarily ground in a ball mill,
after which the powder obtained is separated into narrow fractions
by column sedimentation in 0.1M sodium chloride solution. Fractions
required for a given type of sensor are collected, for example, for
polycapillary tubes with isolated channels of 20 micron size,
fractions are collected with limiting grain size of 15-17
micron.
[0077] B. Workpieces of polycapillary columns 9 (lengths of
straight polycapillary tubes) are fastened in clamps 10 of an
adjustable height holder 11 sliding over the stand 12 mounted on
stationary frame 13 (FIG. 4). By means of holder 11 polycapillary
columns 9 are immersed to the half of their length into vessel 14
containing organic liquid, placed on movable stage 15, mounted in
its turn on a frame 13. Stage 15 may travel on guide rollers 16
both in free and in controlled indexing mode.
[0078] Organic liquid should possess following properties:
[0079] it should be wetting the material of microchannels walls of
polycapillary columns, but to a lesser extent than water;
[0080] liquid shouldn't be miscible with aqueous phase;
[0081] liquid should be lighter than water.
[0082] For example, hexane may be selected as such liquid. All
columns are completely filled with hexane over the course of 5 min.
due to capillary forces.
[0083] C. Mass of a number of sorbent particles corresponding to
the number of channels is calculated and weighed out beforehand.
For example, in order to place one sorbent granule into each
20-micron microchannel in polycapillary column having 400,000
microchannels, it is necessary to have 1 mg of sorbent fraction
having particle size 15-18 micron and density 1.1 g/cm3; to make
simultaneously 100 sensors, it is necessary to have 100 mg of
sorbent.
[0084] D. Working suspension is prepared. To the weighed amount of
sorbent placed into glass microvessel 17 equipped with automatic
drop feeder 18 and mixing microdevice 19, 100 drops (by the number
of sensors manufactured) (5.times.10-2 cm3 each) of concentrated
sodium chloride solution having density equal to density of
sorbent, are introduced with another liquid metering unit (dropper)
and the mixture is agitated to obtain stable suspension.
[0085] E. Use is made of hydrophobic plate 20 (for example, made of
polyethylene) positioned on movable stage 15 with wells 21 cut out
in the form of truncated cone, their arrangement and spacings
corresponding to positions of clamps 10 of the holder 11 and
distances between them. By adjusting advance of centers of conical
wells 21 to the suspension microfeeder 18 and performing
coordinated dosing of drops, one drop of suspension is placed into
each one of 100 wells.
[0086] F. Level of holder 11 is lifted for a short time, glass
vessel 14 containing hexane is drawn aside, hydrophobic plate 20
with suspension drops in conical wells 21, mounted on movable stage
15, is placed under the holder and the stage is fixed in a strictly
calculated position. The holder 11 is pulled down in such a way
that the lower end of each polycapillary column 9 would come into
contact with corresponding drop of suspension. In the course of ca.
30 s suspension is drawn (total drop without remainder) into the
column due to capillary forces.
[0087] Photomicrographs of the lower end face of column taken at
different magnification scales, shown in FIG. 5, allow to
demonstrate scheme of sorbent grain 22 inclusion into isolated
microchannel 23 of the multichannel structure.
[0088] G. The upper end faces of polycapillary columns are sealed
by one of methods described in Tables 1 or 2.
[0089] H. The lower part of each ready sensor is covered with
special cap 24 (FIG. 6) having side walls made of a length 25 of
silicone tube, tightly adjoining the outer wall of polycapillary
column 9. Bottom of the cap 24 is formed by a net or microporous
membrane 26 stretched over plastic cylindrical ring 27 and glued,
as shown in FIG. 6, with one side to the outer surface of said
cylindrical ring 27, and with the other side--to internal surface
of a length 25 of silicone tube. Examples of corresponding nets or
membranes are listed in Table 5. In particular, 10-micron nylon
screen filter is used (standard Millipore product). This variant is
used in the case when sorbent microgranules are larger than 10
micron in size. In all the other embodiments, a membrane is used
instead of screen microfilter, for example, polyacetate membrane
having micropores of 5 micron or less (standard Millipore product),
selected in accordance with dimensions of sorbent microgranules.
Before mounting the cap on the lower part of sensor, the internal
surface of silicone tube, directly adjoining the external surface
of polycapillary tube, is coated with a thin layer of polymerizing
water-repellent sealant (adhesive).
[0090] Manufacturing of device with solid organic layer, for
example, paraffin, comprises the above stages A, C, D, E, and H,
and differs in embodiment of stages B and F (see below,
correspondingly, B 1 and F 1), as well as in the stage G being
omitted.
[0091] B1. Workpieces of polycapillary columns are immersed using
adjustable height holder 11 (FIG. 4) into vessel 14, placed on
movable stage 15 and containing molten paraffin instead of hexane,
to a level by 1-2 mm below the upper end face of columns. Paraffin
is melted and maintained in the molten state due to heat-exchange
tube 28 being inserted into the vessel, with hot water (or silicone
oil) supplied from an external thermostat.
[0092] In the course of 30 min. all columns are completely filled
up with liquid paraffin due to capillary forces. After that,
polycapillary columns are raised to such a level that only lower
part of polycapillary columns with no more than 3 cm height would
remain in liquid. The system is maintained in this position for 10
min., permitting the paraffin in non-immersed part of the columns
to cool down and solidify.
[0093] F1. Level of holder 11 is lifted for a short time, glass
vessel 14 containing liquid paraffin is drawn aside by moving the
stage 15, and hydrophobic plate 20 with suspension drops is placed
under the holder and fixed in a strictly calculated position. The
holder 11 is pulled down in such a way that lower end of each
polycapillary column would come into contact with corresponding
drop of suspension. Due to reduction of paraffin volume on cooling
and solidification (by approximately 5%) in the lower part of the
columns, the suspension drop is drawn completely into the column in
the course of ca. 300 s (without remainder).
[0094] Manufacturing of the device comprising different sorbents
(fluorescent chip) with liquid or solid organic layer is similar to
the above embodiments and differs only in realization of stages C
and D (see below, correspondingly, C1 and D1)
[0095] C1. Mass of a number of sorbent particles corresponding to
the number of channels is calculated and weighed out beforehand.
For example, if using 10 different sorbents and selecting
polycapillary tube having 400,000 of 20-micron channels, it is
necessary to have 100 .mu.g of each sorbent (see Table 4) with
particle size 15-18 micron and density 1.1 g/cm3. To make 100
sensors simultaneously, it is necessary to have 10 mg of each
sorbent.
[0096] D1. Working suspension is prepared. 100 drops (510-2 cm3
each) of concentrated sodium chloride solution with density equal
to the density of sorbent are introduced to the weighed amount of
sorbent mixture, placed into glass microvessel 17 equipped with
automatic drop feeder 18 and mixing microdevice 19, with the help
of another similar dosing unit, and the mixture is agitated to
obtain stable suspension.
[0097] The process of sensors manufacturing comprises stage of
their selective testing to determine content of working sorbent and
rate of sensors functioning.
[0098] The sensor under test is kept for 10 min. in a beaker with
0.1N hydrochloride acid solution (while agitating the solution) and
then washed three times in distilled water. pH meter is used to
ascertain that pH of the distilled water remains unchanged in the
presence of sensor.
[0099] After that, sensor is put into a beaker with 20 ml of 0.01N
NaCl solution placed under the pH-meter, and changes in solution pH
with time are followed under continual stirring. Such a change,
namely, acidification of the solution, takes place due to ionic
exchange Na+--H+. Testing is repeated at least twice in order to
ascertain reproducibility of the results. FIG. 7 demonstrates that
the results are virtually completely reproduced. The time to
attainment of plateau region on the curves presented (ca. 7 min.)
corresponds to equilibration time, that is, is indicative of
kinetic characteristics of the sensor, while drop in pH value shows
exchange capacity. It is seen from curves in FIG. 7, that this drop
corresponds to a change from pH=6.8-7.0 to pH=3.60-3.75. In terms
of exchange capacity, it corresponds to 4.3-4.4 .mu.g-eq, and
taking into account tabulated capacity of KU-2 cationite, equal to
4-4.5 mg-eq/g, it may be seen that 1 mg of cationite is
"working".
[0100] The sensors obtained may be used for analytical control of
different solutions. Examples of control units design are shown in
FIG. 8-11. In these Figures: 29--flow-through cell; 30--sensor;
31--vessel with solution being tested; 32--pump; 33--ultrasonic
sorption activator; 34--X ray excitation source of X-ray
fluorescent spectral analyzer; 35--X-ray fluorescent sensor;
36--signals converter; 37--computer; 38--source of UV radiation (UV
laser); 39--waveguide for UV excitation; 40--luminescence sensor;
41--luminescent spectral analyzer; 42--sensor with radiolucent
layer of organic substance, made of curved polycapillary tube;
43--sensor with a layer of optically transparent organic substance,
made of a length of polycapillary tube in the form of a tablet;
44--waveguide for luminescent radiation in the visible region.
[0101] Operation of sensors incorporated into analytical units
specified is described below.
[0102] When utilizing X-ray fluorescence method, flow-through
solutions consisting of flushing waste waters of electroplating
manufacture (copper and zinc plating) after production stage of
their purification by ionic exchange have been selected as control
object for analysis. Content of non-ferrous and heavy metal ions in
such purified solutions doesn't exceed few tens of .mu.g/l.
Therefore, these purified solutions are allowed to be discharged to
natural water reservoirs of fishing industry use.
[0103] At the same time, detection limits of X-ray fluorescence
method in direct solution analysis are at the level of several tens
of mg/l.
[0104] The solution tested from vessel 31 had been passed with pump
32 in the course of 30-120 min. through cell 29 with sensor 30
immersed (FIG. 8). After said treatment, corresponding spectra have
been registered with X ray fluorescent device "Focus" [14]. To
desorb accumulated elements and restore sensor for use in
subsequent analyses, the sensor was immersed with its lower end
(containing sorbent) into 0.1N hydrochloric acid solution and held
in it for 15 min.
[0105] FIGS. 12-14 demonstrate X ray fluorescence spectra
registered with apparatus shown schematically in FIG. 8 utilizing
sensors made of straight lengths of polycapillary tubes of 10 cm
height employing as a layer of organic substance paraffin (FIG. 12
and FIG. 14) and hexane (FIG. 13) layers for following variants of
sensor make:
[0106] in FIG. 12 sensors are made of lead glass, comprise 400,000
microchannels having diameter of isolated microchannel 20 micron
and walls thickness between them 2 micron, each one containing
microgranule of 16 micron in size made of strong-acid cationite
KU-2 on basis of styrene and divinylbenzene with sulphonic
functional groups;
[0107] in FIG. 13 sensors are made of lead glass, comprise
1,000,000 microchannels having diameter of isolated microchannel 10
micron and walls thickness between them 1 micron, each channel
containing microgranule of 8 micron in size made of strong-acid
cationite KU-2 on basis of styrene and divinylbenzene having
suphonic functional groups;
[0108] in FIG. 14, sensors are made of leadless glass, comprise
1,000,000 microchannels having diameter of isolated microchannel 10
micron, each channel containing microgranule of 8 micron in size
made of weak-acid cationite KB-4 on basis of polymethylmethacrylate
with carboxylic functional groups.
[0109] Concentrations of components being determined in washing
water, found at different time periods utilizing fluorescent
sensors, amount to: in FIG. 12: Fe--30 .mu.g/l; Cu--90 .mu.g/l;
Ni--60 .mu.g/l; Mn--200 .mu.g/l; Co--320 .mu.g/l, Zn--120 .mu.g/l,
total time of accumulation and analysis--30 min.; in FIG. 13, 14:
Cu--50 .mu.g/l; Fe--30 .mu.g/l; Zn--50 .mu.g/l, total time of
accumulation and analysis--120 min.
[0110] As it is seen from spectra presented, use of fluorescent
sensors proposed according to the invention allows to determine
with confidence components content, 1,000 times smaller than that
attainable for direct analytical control without sensors, thus
bringing the X-ray fluorescence method to the level of methods for
monitoring natural and waste waters.
[0111] Fluorescent sensors intended for use in the region of
visible luminescence, excited by ultraviolet radiation supplied to
the end face containing sorbent microgranules, are utilized as a
part of analytical device shown in FIG. 9. Analysis of continuous
flow solutions containing organic luminophors or biologically
active molecules with crosslinked luminescently active probes is
performed by technique similar to that described above for X ray
fluorescence, except that the most appropriate source of the
exciting radiation is a UV-laser, and registering
instrument--luminescent spectral analyzer. The detection limits of
the components (organic or biologically active substances) being
determined with use of said sensors decrease in proportion to
accumulation coefficient of corresponding sorbents, listed in line
10 of Table 4, namely, by a factor of 102-104.
[0112] Fluorescent sensors made of a curved length of polycapillary
tube having radiolucent or UV-transparent upper layer and internal
radiolucent or UV-transparent layer of organic substance, are used
in analytical device shown in FIG. 10.
[0113] Fluorescent sensors made of a length of polycapillary tube
in the form of a tablet with UV-transparent upper layer and
internal UV-transparent layer of organic substance are used in
analytical device shown in FIG. 11.
[0114] Analysis of continuous flow solutions containing components
being determined, in particular, non-ferrous and heavy metals, as
well as luminescently active organic and biological substances, is
performed by techniques similar to those described above, except
that, as shown in Figures specified, the exciting X ray radiation
from source 34 is supplied to the side of the end face not
submerged into solution analyzed (FIG. 10), or except that the
luminescent radiation in the visible region is transported to
sensor 40 with the help of a waveguide 44 (FIG. 11).
[0115] The detection limit of the components being determined using
said sensors decreases in proportion to accumulation coefficient of
corresponding sorbents, described in Table 4. In particular, the
detection limit of metals decreases 103-105 times, and that of
organic and biologically active substances--102-104 times.
[0116] Fluorescent sensors having different sorbents located in
microchannels, namely, fluorescent chips, are used in analytical
devices similar in design to those shown in FIG. 8-11. However,
sensor 35 in FIG. 8 and FIG. 10 is a raster (two-coordinate) X ray
sensor, while sensor 40 in FIG. 9 and FIG. 11 is a two-coordinate
sensor in the visible region (electronic photocamera). When using
X-ray fluorescence method, the analytical result for each
characteristic X ray fluorescence band of chemical element
determined is brought out in the form of three-dimensional diagram:
signal intensity vs. sorbent microgranules coordinates (position)
in the end face of a sensor (chip).
[0117] When utilizing luminescence in the visible region, the
analytical result for each luminescence wavelength of organic or
biological compound being determined, containing luminophor, or
each de-excitation wavelength of luminophor contained in sorbents,
characteristically shifted under the influence of inorganic or
organic component determined (adsorbed), is brought out in the form
of three-dimensional diagram: light signal intensity versus sorbent
microgranules coordinates in the end face of a sensor (chip).
[0118] Processing of test results in these cases is performed by a
procedure similar to that described in [10].
[0119] The embodiments described hereinabove are further intended
to explain best modes known of practicing the invention and to
enable others skilled in the art to utilize the invention in such,
or other, embodiments and with the various modifications required
by the particular applications or uses of the invention.
[0120] Accordingly, the description is not intended to limit the
invention to the form disclosed herein. Also, it is intended that
the appended claims be construed to include alternative
embodiments.
SOURCES OF INFORMATION
[0121] 1. G. K. Budnikov, What is chemical sensors//Soros
Educational Journal, 1998, No. 3, P. 72-76 (in Russian).
[0122] 2. Fluorescent Chemosensors for Ion and Molecule
Recognition, ACS Symp. Ser./ed. A. W. Czarnik//AChS Publ.,
Washington, D.C. 1992, 225 p.
[0123] 3. Reviews: The Chipping Forecast//Nature Genetics, 1999, V.
21, P. 1-60.
[0124] 4. Gilbert W., DNA sequencing and gene structure/Science,
1981, V. 214, P. 1305-1312.
[0125] 5. V. Barskij, A. Kolchinskij, Yu. Lysov, A. Mirzabekov,
Biological microchips containing nucleic acids, proteins and other
compounds immobilized in hydrogel: properties and applications in
genomics//Molekulyarnaya Biologiya (Molecular Biology), 2002, T.
36, P. 563-584 (in Russian).
[0126] 6. S. Ampuero, J. O. Bosset, The electronic nose applied to
dairy products: a review//Sensors and Actuators B: Chemical, 2003,
V. 94, P. 1-12.
[0127] 7. Seitz W. R., Fiber optic sensors/Anal. Chem., 1984, V.
86, No. 1, P. 16-25.
[0128] 8. Patent of Russian Federation No. 2157385, publ. Oct. 10,
2000.
[0129] 9. P. Zhang, T. Beck, W. Tan, Design a molecular beacon with
two dye molecules, Angewandte Chemie International Edition, 2001,
V. 40, P. 402-405.
[0130] 10. U.S. Pat. No. 6,023,540, publ. Feb. 8, 2000.
[0131] 11. Patent of Russian Federation No. 2096353, publ. Nov. 20,
1997.
[0132] 12. Patent of Germany No. 4411330, publ. Aug. 14, 2003.
[0133] 13. Patent of Russian Federation for utility model No.
31859, publ. Aug. 27, 2003.
[0134] 14. A. S. Scherbakov, S. M. Cheremisin, V. V. Danichev, V.
S. Ozerov, Focus-1 X-ray fluorescent spectrometer, Proceed. SPIE,
2000, V. 4155, P. 131-137.
[0135] 15. V. A. Arkad'ev, A. P. Kolomijtsev, M. A. Kumakhov, I.
Yu. Ponomarev, I. A. Khodeev, Yu. P. Chertov, I. M. Shakhparonov.
Wide-band X-ray optics with a large angular aperture. Uspekhi
Fizicheskikh Nauk (Advances in Physical Sciences), March 1989 r.,
V. 157, Issue 3, p. 529-537 (in Russian).
[0136] 16. U.S. Pat. No. 5,192,869, publ. Mar. 09, 1993.
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